The prevalence of overweight and obesity reaches approximately 30% in industrialized countries, and obesity together with the related metabolic disorders, insulin resistance and type II diabetes mellitus (T2D) are ever growing and major health problems. Like obesity, T2D has a strong genetic component and is thought to be the result of the interaction of polygenes with the environment. Consequently, genes with a major effect have yet to be identified in humans. In contrast, cloning of obesity and diabetes genes in the mouse is much easier and remarkable progress has been made in the identification of the genes mutated in mouse models of obesity. The real value of the mouse mutations lies in the access they provide to novel metabolic and regulatory pathways involved in the etiology of diabesity and related disorders in humans. New models that will define or identify novel T2D pathways are needed to further our understanding of this chronic and often life threatening disease. We are in a unique position at The Jackson Laboratory to discover and develop new obesity/type 2 diabetes models and have the proven expertise to identify their underlying molecular bases. In the past we have established, and biochemically and genetically characterized, a unique new mouse model for type II diabetes, the TallyHo (TH) strain. The TH strain is characterized by glucose intolerance, hyperinsulinemia, chronic hyperglycemia, increased body weight and reduced activity levels. TH is currently the only model in which a spontaneous single gene mutation, tanidd1, triggers T2D. In addition, reminiscent of the situation in humans, the major locus interacts with additional background obesity and diabetes susceptibility genes to produce overt diabetes. To facilitate positional cloning and to evaluate the contribution of the interacting genes to the overall phenotype, we have generated resources in the form of congenic strains on the common B6 background. We have also identified a robust molecular subphenotype for tanidd1, making its identification by positional cloning feasible. In order to gain new insights into T2D pathways we propose to: a) positionally clone the diabetes susceptibility gene tanidd1 present in TH; b) generate new models for subphenotypes of T2D in the form of congenic strains derived from TH and characterize them physiologically; c) determine what phenotypic consequences the interactions between these genes have. At the successful conclusion of this work, we will have identified a novel diabetes susceptibility gene and provided new, well characterized models of T2D subphenotypes that will lead to new insights into the etiology of T2D.